Process for preparing alpha-methyl-beta-(3,4-dihydroxyphenyl)-alanine

ABSTRACT

1-(X-CH2-),3-(R1-O-),4-(R2-O-)BENZENE   WHEREIN EACH OF R1 AND R2 IS LOWER ALKYL, OR R1 AND R2 ARE COMBINED TOGETHER TO FORM A METHYLENE RADICAL AND X IS HALOGEN, TO PRODUCE A COMPOUND OF THE FORMULA:   1-(R-OOC-C(-CH3)(-CN)-CH2-),3-(R1-O-),4-(R2-O-)BENZENE   A LOWER ALKYL ESTER OF A-ISOCYANO-PROPIONIC ACID IS CONDENSED WITH A COMPOUND OF THE FORMULA: WHEREIN R IS LOWER ALKYL, AND R1 AND R2 ARE AS DEFINED ABOVE. A-METHYL-B-(3,4-DIHYDROXYPHENYL)-ALANINE IS OBTAINED BY HYDROLYZING THE COMPOUND (II) WITH CONCENTRATED MINERAL ACID. ALTERNATIVELY, A-METHYL-B-(3,4-DIHYDROXYPHENYL)-ALAMINE MAY BE OBTAINED BY HYDROLYZING COMPOUND (II) WITH DILUTE MINERAL ACID TO PRODUCE THE CORRESPONDING A-METHYL-B-PHENYLALANINE ESTER, HYDROLYZING THE ALANINE ESTER WITH A ALKALI METAL HYDROXIDE TO PRODUCE THE CORRESPONDING A-METHYL-B-PHENYLALANINE, AND THEN HYDROLYZING SOME WITH CONCENTRATED MINERAL ACID.

United States Patent 3,784,640 PROCESS FOR PREPARING u-METHYL-fi-GA-DIHYDROXYPHENYL)-ALANINE Kentaro Okumura, Kobe, and Kazuo Matsumoto andMamoru Suzuki, Osaka, Japan, assignors to Tanabe Seiyaku Co., Ltd.,Osaka, Japan No Drawing. Filed Dec. 14, 1971, Ser. No. 207,950 Claimspriority, applicafion Japan, Dec. 29, 1970, 46/129,807 Int. Cl. C07c101/72 US. Cl. 260-519 11 Claims ABSTRACT OF THE DISCLOSURE A loweralkyl ester of wisocyano-propionic acid is condensed with a compound ofthe formula:

IR 0 CHzX wherein each of R and R is lower alkyl, or R and R arecombined together to form a methylene radical and X is halogen, toproduce a compound of the formula:

wherein R is lower alkyl, and R and R are as defined above.u-Methyl-fi-(3,4-dihydroxyphenyD-alanine is obtained by hydrolyzing thecompound (H) with concentrated mineral acid. Alternatively,a-methyl-fi-(3,4-di hydroxyphenyD-alanine may be obtained by hydrolyzingcompound (II) with dilute mineral acid to produce the correspondinga-methyl-B-phenylalanine ester, hydrolyzing the alanine ester with analkali metal hydroxide to produce the correspondinga-methyl-p-phenylalanine, and then hydrolyzing some with concentratedmineral acid.

This invention relates to a process for preparingamethyl-,8-(3,4-dihydroxyphenyl)-alanine.

u-Methyl-B-(3,4-dihydroxyphenyl)-alanine (hereinafter designated asa-methyl DOPA) is useful as an anti-hypertensive agent.

Several methods of producing a-methyl DOPA are known. For example, it isprepared from 3,4-dimethoxyacetonitrile viaa-methyl-a-amino-fi-(3,4-dihydroxyphenyl)-propionitrile orS-methyl-S-(3,4-dimethoxyphenyl)- hydant-oin (Journal of the AmericanChemical Society, vol. 77 (1955), page 700). Alternatively, a-methylDOPA may be prepared from safrole via5-methyl-5-(3,4-methylenedioxyphenyl)-hydantoin (Japanese patentpublication No. 11,211/1964). We have now found a novel method forpreparing a-methyl DOPA in a higher yield.

According to the present invention, a-methyl DOPA can be prepared bycondensing a lower alkyl ester of wisocyano-propionic acid with a benzylhalide compound of the formula:

R oomx wherein each of R and R is lower alkyl, or R and R are combinedtogether to form a methylene radical and X 3,784,640 Patented Jan. 8,1974 ice NC R20 vtgherein R is lower alkyl, and R and R are as defined aove.

The condensation reaction of the invention can be carried out in thepresence of a basic catalyst in a suitable solvent. Preferred examplesof said catalyst include an alkali metal (e.g., sodium metal,potassiummetal), an alkali metal alkoxide (e.g., sodium methoxide, sodiumethoxide, potassium methoxide), an alkali metal hydride (e.g., sodiumhydride, potassium hydride), an alkali metal amide (e.g., sodium amide,potassium amide) and an alkali metal salt (e.g., sodium cyanide,potassium cyanide, sodium bicarbonate, sodium carbonate).Tetrahydrofuran, dioxane, benzene and toluene are suitable as thereaction solvent. It is preferred to carry out the reaction at 0 to 60C., especially at 30 to 40 C. The reaction product thus obtained can beemployed in the subsequent step without isolation and/or purification.If required, however, the product (Il) may be recovered in a pure state.The isolation and/0r purification thereof may be conducted in aconventional manner.

The hydrolysis of the present invention can be carried out as follows.oz-Methyl-a-isocyano-fi-phenyl-propionate compound (II) may be directlyconverted to a-methyl DOPA by hydrolyzing said propionate withconcentrated mineral acid under heating. The reaction is preferablycarried out at 70 to 130 C., especially at to C. An aqueous solutioncontaining more than 20 -w./-w. percent of hydrochloric, hydrobromic,hydroiodic or sulfuric acid is employed as the concentrated mineralacid.

Alternatively, a-methyl-u-isocyano-B-phenyl-propionate compound (II) maybe hydrolyzed with dilute mineral acid to produceu-methyl-3-phenyl-alanine ester compound of the formula:

CH3 R10 CH;(EC O O R wherein R, R and R are as defined above. In thisalternative method, it is preferred to carry out the reaction at 30 to60 C., especially at 40 to 50 C. An aqueous solution containing lessthan 10 W./'W. percent of hydrochloric, hydrobromic, hydroiodic orsulfuric acid is suitably employed as the dilute mineral acid.Furthermore, an alkanol of one to four carbon atoms (e.g., methanol,ethanol), an alkanoic acid of one to four carbon atoms (acetic acid,formic acid), water or mixture thereof may be employed as the reactionsolvent. If required, the intermediate product (III) thus obtained maybe further subjected to partial hydrolysis with an alkali metalhydroxide to produce a-methyl-fi-phenyl-alanine compound of the formula:

wherein R and R are as defined above. The hydrolysis with alkali metalhydroxide is preferably carried out at 20 to 60 C., especially at 40 to50 C. Suitable examples of the alkali metal hydroxide include potassiumhydroxide and sodium hydroxide. Water and an aqueous alkanol such asaqueous methanol or aqueous ethanol are suitable as the reactionsolvent.

The reaction products (111) and (IV) thus obtained may be readilyconverted to a-methyl DOPA by hydrolyzing each of said products with theaforementioned concentrated mineral acid under heating at 70 to 130 C.,especially at 90 to 110 C. a-Methyl DOPA may be recovered from thereaction solution in a conventional manner.

Practical and presently-preferred embodiments of the present inventionare shown in the following examples.

EXAMPLE 1 A mixture of methyl a-isocyano-propionate, 37.65 g. of3,4-dimethoxybenzyl bromide and 135 ml. of tetrahydrofuran is addedgradually, at room temperature and under stirring, to a suspension of6.3 g. of 69% sodium hydride in 225 ml. of tetrahydrofuran. Theresultant mixture is stirred for 2 hours at the same temperature. Afterthe reaction is completed, the mixture is evaporated to remove solvent.The residue thus obtained is dissolved in ethyl acetate. The ethylacetate solution is washed with water, dried and then evaporated toremove solvent. 41.8 g. of methyla-methyl-a-isocyano-B-(3,4-dimethoxyphenyl)-propionate are obtained.

30.1 g. of the methyla-methyl-a-isocyano-p-(3,4-dimethoxyphenyl)-propionate are dissolved in140 ml. of a mixture of 2 N-hydrochloric acid and methanol. The solutionis heated at 50 C. for an hour. Then, the reaction solution isconcentrated under reduced pressure to remove solvent. Ether is added tothe residue and the crystalline precipitates is collected by filtration.39 g. of amethyl-B-(3,4 dimethoxyphenyl)-alanine methyl esterhydrochloride are obtained.

Nuclear magnetic resonance spectrum (in D r: 3.5 (m., 3H), 6.35 (S, 3H,COOCH 6.4 (S, 6H, OCH 7.1 (d., 2H, CH 8.55 (S, 3H, CH

Thin layer chromatography: R,-value=0.7 (on a silicagel plate: Solvent,chloroform-methanol-acetic acid The 39 g. ofa-methyl-p-(3,4-dimethoxyphenyl)-alanine methylester hydrochloride aredissolved in 290 ml. of 1 N-sodium hydroxide solution. The resultantsolution is allowed to stand for 12 hours at room temperature. Thesolution is washed with benzene, and then adjusted to pH 8 withconcentrated hydrochloric acid. The crystalline precipitate is collectedby filtration. The crystals are washed with water. 29 g. ofa-methyl-B-(3A-dimethoxyphenyD-alanine are obtained. Yield: 90% M.P.271- 273 C. (decomp.).

Nuclear magnetic resonance spectrum (in CF COOD): 1'! 3.0 (S, 3H,aromatic), 5.5 (q., 2H, -CH 6.0 (S, 6H, OCH;,), 8.0 (S, 3H, C-CHg).

6.0 g. of the u-methyl-fi-(3,4-dimethoxyphenyl) alanine are dissolved in100 ml. of 48% hydrobromic acid. The resultant solution is refluxed for8 hours in nitrogen atmosphere. Then, the solution is concentrated underreduced pressure in nitrogen atmosphere. Water is added to the residue,and the aqueous solution is concentrated under reduced pressure toremove hydrobromic acid (this operation is repeated three times). Theresidue thus obtained is dissolved in 50 ml. of water. The aqueoussolution is adjusted to pH 6.5 with concentrated aqueous ammonia. Sulfurdioxide gas is introduced into the aqueous solution to decolorize it.Then, the solution is concentrated to 40 ml. in nitrogen atmosphere. Theconcentrated solution is allowed to stand over night, and thecrystalline precipitate is collected by filtration. 4.3 g. ofa-methyl-B- (3,4-dihydroxyphenyl)-alanine are obtained. M.P. 298- 300 C.(decomp.). The physicochemical properties of this product are identicalwith those of an authentic sample.

EXAMPLE 2 A mixture of 3.33 g. of methyl a-isocyanopropionate, 7.08 g.of 3,4-methylenedioxybenzyl bromide and 30 m1. of tetrahydrofuran isadded gradually, at room temperature and under stirring, to a suspensionof 1.39 g. of 69% sodium hydride in 50 ml. of tetrahvdrofuran. The

resultant mixture is stirred for 2 hours at the same temperature. Afterthe reaction is completed, the mixture is evaporated to remove solvent.The residue thus obtained is dissolved in ethyl acetate. The ethylacetate solution is washed with water, dried and then evaporated toremove the solvent. 7.0 g. of methyl a-methyl-a-isocyano-p-(3,4-methylenedioxyphenyl)-propionate are obtained.

Infrared absorption spectrum:

will: 2130 (N=C), 1750 (COOCH cm."

5.0 g. of the methyla-methyl-a-isocyano-fl-(3,4methylenedioxyphenyl)-propionate aredissolved in 50 ml. of a mixture of 2 N-hydrochloric acid and methanol.The resultant solution is heated at 50 C. for 30 minutes. Then, thereaction solution is concentrated under reduced pressure to remove thesolvent. Methanol is added to the residue. The methanol solution isconcentrated to dryness under reduced pressure. Ether is added to theresidue, and the crystalline precipitate is collected by filtration. Thecrystals are recrystallized from a mixture of ethanol and ether. 5.3 g.of u-methyl- -(3,4-methylenedioxyphenyl)- alanine methyl esterhydrochloride are obtained. Yield:

Nuclear magnetic resonance spectrum (in D 0):

6.2(S, 3H, COOCH 6.9(d, 2H, CHI 8.45(S, 3H, CH

2.7 g. of the a-methyl-fi-(3,4methylenedioxyphenyl)- alanine methylester hydrochloride are dissolved in 17 ml. of 1 N-sodium hydroxidesolution. The resultant solu tion is allowed to stand for 12 hours atroom temperature. The solution is adjusted to pH 8 with concentratedhydrochloric acid. Crystalline precipitate is collected by filtration.0.85 g. of a-methyl-p-(3,4-methylenedioxyphenyl)-alanine is obtained.Yield: 95% M.P. 266-268 C. (decomp.)

0.8 g. of the a-methyl-fl-(3,4-methylenedioxyphenyl)- alanine isdissolved in a mixture of 5 m1. of acetic acid and 15 ml. of 48%hydrobromic acid. The solution is refluxed for 6 hours in nitrogenatmosphere. Then, the solution is concentrated under reduced pressure innitrogen atmosphere. Water is added to the residue, and the aqueoussolution is concentrated under reduced pressure to remove hydrobromicacid. The residue thus obtained is dissolved in 3 ml. of water. Theaqueous solution is adjusted to pH 6.5 with a concentrated ammonia.Sulfur dioxide gas is introduced into the aqueous solution to dicolorizeit. The aqueous solution is concentrated to one ml. in nitrogenatmosphere. Then, the concentrated solution is adjusted to pH 6.5 withconcentrated ammonia. Ethanol is added to the solution, and thecrystalline precipitate is collected by filtration. 0.5 g. of a-methyl-13-(3,4-dihydroxyphenyl)-alanine is obtained. M.P. 298- 300 C.(decomp.). The physico-chemical properties of this product are identicalwith those of an authentic sample.

What we claim is:

i1. A process for preparing a-methyl-fl(3,4-dihydroxyphenyl)-alaninewhich comprises the steps of (A) condensing a lower alkyl ester ofu-isocyanopropionic acid with a compound of the formula:

R 0 H X wherein each of R and R is lower alkyl or R and R are combinedtogether to form a methylene radical and X is halogen, to produce acompound of the formula:

on, R CHn-O-C 0 OR R20 NC wherein R is lower alkyl, and R and R are asdefined above, said condensation being carried out at a temperature of 0to 60 C., in the presence of a basic catalyst selected from the groupconsisting of alkali metals, alkali metal alkoxides, alkali metalhydrides, alkali metal amides, and alkali metal salts, and in a solventselected from the group consisting of tetrahydrofuran, dioxane, benzeneand toluene, and

(B)(a) hydrolyzing the compound (II) with concentrated mineral acid, ata temperature of 70 C. to 130 C., saidu-methyl-fi-(3,4-dihydroxyphenyl)- alanine, or

(b) hydrolyzing the compound (II) at a temperautre of 30 to 60 C. and ina reaction solvent selected from the group consisting of alkanols having1 to 4 carbon atoms, alkanoic acids having 1 to 4 carbon atoms, water,and mixtures thereof, with dilute mineral acid to produce a compound ofthe formula:

(III) wherein R R and R are as defined above, and hydrolyzing thecompound (III) with concentrated mineral acid at a temperature of 70 to130 C. to produce said a-methyl-fl-(3,4-dihydroxyphenyl)- alinine orhydrolyzing compound (III) with an alkali metal hydroxide at atemperature of 20 to 60 C. and in water or aqueous alkanol, to produce acompound of the formula:

CH: mooHi :J-0 0 OH R20 NH:

wherein R and R are as defined above and then hydrolyzing the compound(IV) with concentrated mineral acid at a temperature of 70 to 130 C. toproduce said a methyl 8-(3,4dihydroxyphenyl)- alinine.

2. The process according to claim 1 wherein the basic catalyst issodium, potassium, sodium ethoxide, potassium methoxide, sodium hydride,potassium hydride, sodium amide, potassium amide, or sodium carbonate.

3. The process according to claim 1 wherein the condensation reaction iscarried out at 30 to 40 C.

4. The process according to claim 1 wherein the hydrolysis of thecompound (II), (III) or (IV) with concentrated mineral acid is carriedout at to C.

5. The process according to claim I wherein an aqueous solutioncontaining more than 20 w./w.% of hydrochloric, hydrobromic, hydroiodicor sulfuric acid is employed as the concentrated mineral acid.

6. The process according to claim 1 wherein the hydrolysis of thecompound (II) with dilute mineral acid is carried out at 40 to 50 C.

7. The process according to claim 1 wherein an aqueous solutioncontaining less than 10 W./W. percent of hydrochloric, hydrobromic,hydroiodic or sulfuric acid is employed as the dilute mineral acid.

8. The process according to claim 1 wherein the hydrolysis of thecompound (HI) with alkali metal hydroxide is carried out at 40 to 50 C.

9. The process according to claim ll wherein the reaction solventemployed in hydrolyzing the compound (II) with dilute mineral acid isselected from the group consisting of methanol, ethanol, acetic acid,formic acid, water and mixtures thereof.

10. The process according to claim 1 wherein the hydrolysis of thecompound (III) is carried out with an alkali metal hydroxide selectedfrom the group consisting of potassium hydroxide and sodium hydroxide.

11. The process according to claim 1 wherein the hy-- drolysis of thecompound (III) with alkali metal hydroXide is carried out in water oraqueous ethanol.

References Cited UNITED STATES PATENTS 3,712,911 1/ 1973 Schoellkopf260465 R FOREIGN PATENTS 2,063,502 6/ 1972 W. Germany 260519 OTHERREFERENCES Ohta, Chemical Abstracts, vol. 48, p. 4440g (1954).

Angewandie Chemie, vol. 77, pp. 495-500 (1965).

Angew. Chem. International Edition (English), vol. 10(5), 1971, pp.331-33.

March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure,1968, pp. 724-25.

LORRAINE A. WEINBERGER, Primary Examiner R. J. HAGAN, Assistant ExaminerUS. Cl. X.R.

